This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chi Li, PI, Project 6 The aims of this proposal have not changed. They are designed to examine the molecular mechanisms that regulate programmed cell death initiated from the endoplasmic reticulum (ER). Programmed cell death plays an important role in cancer development, and one of the hallmarks of cancer is the inhibition of programmed cell death. Upon a variety of death signals, cells can initiate death pathways from different subcellular compartments. Although much attention has been focused on the death pathway initiated from mitochondria, relatively little is known about the involvement of the ER during programmed cell death. It remains unclear how signals from ER stress are transduced to induce cell death. To address this question, three specific aims are envisioned: 1. Study the mechanisms of releasing death-inducing factors from the ER lumen during ER stress-induced cell death. 2. Investigate the signaling pathway activated by death-inducing factors from the ER. 3. Determine how the ER-specific death pathway communicates with the death pathway initiated from mitochondria.